Taxanes are diterpenes that are widely used in chemotherapy. They were originally discovered in plants of the genus Taxus (yews) and were first derived from these natural sources. Several are now chemically synthesized. Among the taxanes, the best known are paclitaxel (TAXOL) and docetaxel (TAXOTERE), which is a semisynthetic analog of paclitaxel. Taxanes exert their anti-cancer activity by inhibiting tubulin depolymerization in cells, thus inhibiting mitosis.
Parenteral administration by injection is the typical route of administration of taxanes. However, taxanes are substantially insoluble in water and in other commonly used medicinal parenteral organic solvents, which has presented a challenge to formulation for pharmaceutical use. Docetaxel is typically formulated with POLYSORBATE 80 (Tween 80, a nonionic surfactant and emulsifier) to improve solubility. Paclitaxel is typically formulated with the nonionic surfactant CREMOPHOR EL (polyoxyethylated castor oil). Increased toxicity, including hypersensitivity reactions, anaphylaxis and other serious side effects are associated with these excipients. Pre-medication and additional treatment to prevent hypersensitivity is therefore often necessary. Such additional treatment includes hormone treatment, steroid medications, dexamethasone, diphenhydramine and cimetidine. In addition, the patient must be monitored closely for severe allergic reactions, such as observation of blood pressure, breathing rate, and heart rate. Increased toxicity and side effects sometimes restrict the continuation and completion of taxane treatments thus limiting its effectiveness.
The currently available pharmaceutical formulations of taxanes also suffer from unsatisfactory stability. For example, the docetaxel formulation has low stability, and must be stored at or below room temperature protected from light. Alternatively, they need to be stored as a lyophilized solid prior to re-constitution to a liquid for patient administration. In the IV solution docetaxel has a tendency to precipitate, and requires careful handling procedures such as to avoid shaking.
Efforts to improve the safety and efficacy of taxane pharmaceutical formulations, particularly with paclitaxel and docetaxel, have generally focused on liposomal formulations, nano-granules, cross-linking with albumin, and formulation with cyclodextrin based complexes. It has been shown that complexes with cyclodextrin enhance docetaxel stability, enhance its solubility, and can also enhance drug activity and reduce toxic side effects. However, the solubility of docetaxel after complexing with cyclodextrin is still relatively low, and is inconvenient for clinical use due to a requirement for a substantial amount of solvent to solubilize the complex. Further, because cyclodextrin can degrade ester compounds such as docetaxel, stability can be compromised.
Formulations of docetaxel and paclitaxel requiring reduced amounts organic solvent and cyclodextrin have been reported. See U.S. Pat. Nos. 8,481,511 and 8,426,385. These formulations of either docetaxel or paclitaxel in complexes with hydroxypropyl-β-cyclodextrin (HP-β-CD) and/or sulfobutylether-β-cyclodextrin (SBE-β-CD) provide improved water-solubility and stability, as demonstrated by the Ka. To prepare the compositions, paclitaxel or docetaxel is dissolved in ethanol and added to an aqueous solution of cyclodextrin derivatives, stirring until the taxane is dissolved. Ethanol is then removed via reduced pressure to obtain the complex in liquid form. However, the liquid form is physico-chemically unstable and must be lyophilized to obtain a stable solid (i.e., a lyophilized powder) composition. Chemical and physical stability in liquid form, after reconstitution, is limited to 2-3 hours. Because the powder must be reconstituted before use, the risk of exposure of medical personnel to these cytotoxic compounds is increased. In addition, the present inventors have observed that the lyophilized powder cannot be reconstituted in normal saline, as the API has limited physical stability in saline and quickly precipitates. It can however, be reconstituted in dextrose.
Although there has been some success in improving biocompatibility, in vivo tolerance, solubilization and formulation stability, there is still a need for further improvements in these parameters for pharmaceutical taxane compositions, particularly in parenteral formulations. The present invention addresses these needs. In contrast to the prior art cyclodextrin/taxane powders, the stable liquid pharmaceutical compositions comprising taxane/β-cyclodextrin complexes disclosed herein, based on accelerated aging studies, are expected to remain chemically and physically stable at temperatures from 0° C. to ambient temperature for at least one year, and may be diluted for use in either normal saline or dextrose. The present liquid pharmaceutical compositions also represent significant improvements over the prior art in that they do not contain toxic solubilizers such as CREMOPHOR EL and POLYSORBATE 80 (aka TWEEN 80).